JPH0459298B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a cancer removal agent containing vitamin Ds as an active ingredient. As a result of the isolation and identification of vitamin D ₃ metabolites and research on metabolites conducted in recent years by DeLuca and Kodicek et al., the metabolites were 25-hydroxyvitamin D ₃ , 1α,25-dihydroxyvitamin D ₂ , 1α,24 ,25-trihydroxyvitamin _D3
Vitamin Ds such as these have come to be known. It is well known that these metabolites and many derivatives subsequently synthesized promote the ability to transport calcium from the intestinal tract and the ability to mobilize bone minerals, and are useful as therapeutic agents for various diseases based on abnormal calcium metabolism. The present inventors conducted separate research on the pharmacological effects of these vitamin Ds, and surprisingly, without exception, most vitamin Ds were found to be extremely strong against human myeloid leukemia HL-60 cells at low concentrations. We discovered the surprising fact that it has the ability to induce differentiation into macrophages. The ability of this person to induce differentiation into cancer cells has nothing to do with the previously known effect of vitamin D on regulating calcium metabolism, and vitamin D, such as 9,10-secocholestane skeleton or 9,10-secoergostane skeleton This is a property unique to compounds with . The present invention has been completed through further research based on this new knowledge, and is based on vitamin D.
This is an invention of a cancer removal agent containing a vitamin D derivative having a hydroxyl group at the 1α position as an active ingredient. In the present invention, vitamin Ds include, for example, 9,
A compound having a 10-secocholestane skeleton or a 9,10-secoergostane skeleton, specifically vitamin D ₂ , vitamin D ₃ , 25-hydroxyvitamin D ₃ , 25-hydroxyvitamin D ₂ , 22-dehydro-25 -Hydroxyvitamin _D3 , 24,25-dihydroxyvitamin _D3 , 24-hydroxyvitamin _D3 , 25,26-dihydroxyvitamin _D3 , 24-
Oxovitamin _D3 , 25-hydroxy-24-oxovitamin _D3 , 24,24-difluoro-25-hydroxyvitamin _D3 , 24-fluoro- ₂₅ -hydroxyvitamin D3, _2α -hydroxyvitamin D3,
2β-hydroxyvitamin D ₃ , 1β-hydroxyvitamin D ₃ , 1β,25-hydroxyvitamin D ₃ and their corresponding 6,19-epidioxy-9,
10-Secocholesta5(10),7-diene-3β,25-
Examples include diol. Among these vitamin D derivatives, all of the 5,6-cis vitamin Ds are known compounds, such as those described in Japanese Patent Application Laid-open Nos. 50-40551, 500-100043, and 5-
No. 100044, No. 51-26858, No. 51-26859, No. 51
−100055, No. 54-63058, No. 54-103855,
No. 55-11460, No. 55-72185, No. 55-76858,
No. 56-22763, U.S. Patent No. 3565924,
Manufactured according to the descriptions of patent publications No. 3585221, No. 3715374, and No. 3739001. These compounds of the present invention are formulated and administered in a desired form according to conventional methods. The dose is extremely small, and the blood concentration varies depending on the compound, but it is 20 pg.
It is effective at ~10 μg/ml and can be administered as a soft capsule. Experimental example Myeloid leukemia HL-60 cells suspended in RPMI-1640 medium (containing penicillin and streptomycin, supplemented with 10% FBS) were placed in a Falcon micro test plate (96-well flat bottom) at a concentration of ¹⁰⁴ cells/ml.
0.1 ml was dispensed into each well and incubated overnight at 37°C in a flow of air:carbon dioxide (95:5). The next day, the ethanol solution of each sample was added to RPMI-1640.
The solution was diluted 40 times with a medium, and then diluted stepwise by 4 times to prepare solutions with 5 concentrations, and 0.1 ml of each solution was added to each well of the microplate. 37
After culturing for 3 days in a saturated humidity environment in a 95:5 air:carbon dioxide flow, observe the cells that have spread on the bottom of each recess under an inverted phase-contrast microscope. The minimum effective dose of each analyte was determined as an index. Note that HL-60 cells normally have a spherical shape and are floating cells, but when they differentiate into macrophages, they attach and spread on the bottom of the culture vessel. The following table shows the minimum effective amount for this macrophage-altering effect.

[Table] Example 1 25-hydroxyvitamin D ₃ was added to 60 g of ODO (manufactured by Nisshin Oil Co., Ltd., triglyceride of medium chain fatty acids).
Dissolve 1.0mg and 30% sorbitan acid as a stabilizer
In addition, soft capsules containing 1.0 μg of 25-hydroxyvitamin D ₃ per capsule were manufactured using a gelatin-coated soft capsule machine in accordance with a conventional method. Example 2 25-hydroxyvitamin D ₃ in Example 1
Replaced with [6R]-6,19-epidioxy-9,
10-Secocholester-5(10),7-diene-3β,25
-6,19-epidioxy-9,10 per capsule in the same manner using 1.0 mg of diol.
-Secocoresta-5(10),7-diene-3β,25-
Soft capsules containing 1.0 μg of diol were obtained.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ means a hydrogen atom or a hydroxyl group, and R ₂
means a hydrogen atom, a fluorine atom or a hydroxyl group,
_A cancer-removal agent containing vitamin Ds or 6,19 _- epidioxy derivatives of these compounds as an active ingredient.